Leishmaniasis is a chronic parasitic infection of humans that has emerged as a significant health care problem wold-wide. Using a well- characterized mouse model of healing or progressive cutaneous infection in leishmaniasis to investigations on how IL-12 is regulated by the accessory cell receptor protein, CD40. CD40 is activated by antigen-specific T cells bearing the CD40 ligand and induces IL-12 necessary for Th1 CD4+ cellular responses and cure. Our preliminary data demonstrate CD40-dependent increased synthesis of IL-12 in healing leishmaniasis and show that susceptible BALB/c mice underproduce IL-12 due to CD40 dysfunction and/or decreased accessory cell numbers as disease progresses. We hypothesize that a wide range of CD40 dependent responses jointly promote cure, whereas CD40 dysfunction maintains susceptibility. Our second goal is to use insights gained in these studies to design immunotherapies effective against progressive leishmaniasis, a disease mediated by inappropriate Th2 T cell responses that are IL-12 unresponsive. We hypothesize that the T cell response can be "reset" to an IL-12 responsive state by transient CD4+ cell depletion or that in vivo activation of CD40 by soluble ligand or monoclonal antibody will induce therapeutic microbicidal responses and/or restore IL-12 regulatory effects. Preliminary data support the effectiveness of these proposed immunotherapies. Our specific aims are to: 1. Determine the molecular and cellular basis of IL-12 production during healing or progressive leishmaniasis in resistant C57BL/6 and susceptible BALB\c mice. 2. Determine the full range of protective immune responses dependent on CD40. 3. Identify the lesion(s) responsible for strain dependent differences in IL-12 production during leishmaniasis. These aims are significant in that they address biologic mechanisms responsible for coordinating complex immune responses important in defense against intracellular parasitism and implicated in autoimmunity and transplant rejection. The proposed strategies for reversing pathologic Th- 2 cell responses by "resetting" the T cell response are novel approaches that may be widely applicable to immunotherapy of other Th2-mediated diseases, including severe atopic disorders and helminth-induced pathology.